Antivirals

Mechanisms of Antivirals

(1) Block Viral attachment and entry – Amantidine and Rimantidine block influenza virus uncoating

(2) Block Viral nucleic acid synthesis – the mechanism by which most current anti-virals work

(3) Block Viral processing and release – Protease inhibitors for HIV, Neuraminidase inhibitors for influenza

Drugs for Herpes Simplex I and II, Epstein-Barr virus, Cytomegalovirus, and Human Herpes viruses.

Acyclovir

Mechanism – a deoxyguanosine analog which competitively inhibits viral DNA. Requires a viral thymidine kinase (CMV does not have thymidine kinase)

Resistance – The virus becomes resistant by losing thymidine kinase. Once resistant to acyclovir the virus is also resistant to faciclovir and gancylovir.

Clinical use – HSV, VZV, EBV. Used in primary HSV I and II infections, Herpes encephalitis, chronic suppressive therapy for recurrent HSV, primary Varicella in an adult or immuno-compromised host, and Herpes zoster.

Side effects – renal clearance can lead to crystalline nephropathy (reversible with hydration) and neurologic symptoms in the elderly.

Valacyclovir

A prodrug of acyclovir, converted to acyclovir by 1^st pass metabolism. Same as acyclovir but get higher levels.

Famciclovir

A prodrug of penciclovir, a guanosine analog which competitively inhibits viral DNA polymerase. Requires viral thymidine kinase. Same spectrum as acyclovir but higher and prolonged intracellular concentrations allow a longer dosing interval.

Ganciclovir

Mechanism – a deoxyguanosine analog which competitively inhibits viral DNA polymerase. Uses viral thymidine kinase in HSV and a viral protein kinase in CMV.

Clinical use – CMV, HSV, VZV, EBV, Hep B (post transplant), HHV-6, HHV-8 (Karposi sarcoma Herpes virus). Used to prevent CMV in transplant recipients, to treat end organ CMV in immuno-compromised hosts, and has shown some effect at preventing Karposi’s sarcoma in HIV pts being treated with Ganciclovir for CMV retinitis.

Side effects – Myelosuppression, rarely confusion and mild renal insufficiency.

Foscarnet

Mechanism – an inorganic pyrophosphate analog that blocks the pyrophosphate site on viral polymerase.

Does not require a viral enzyme for phosphorylation. Only available IV

Clinical uses – CMV, HSV (including acyclovir resistant strains), VZV, EBV, HHV-8 (KSHV). Used for CMV end organ disease in immunocompromised host, in combination with gancyclovir for CMV encephalitis or polyradiculopathy, and to treat acyclovir resistant HSV and VZV.

Side effects – Nephrotoxic (reversible), Nausea and vomiting

Cidofovir

Mechanism – a deoxycytidine analog that inhibits viral DNA polymerase. Needs cellular enzymes to work

Administered IV only. Renal clearance that can be inhibited with Probenecid allowing for once a week dosing.

Clinical uses – approved only for treatment of CMV retinitis but has activity against thymidine kinase deficient HSV, as well as EBV, VZV, and adenovirus.

Side effects – irreversible nephrotoxicity, neutropenia, and ocular hypotomy (decreased pressure in eyeball) when put in eye.

Drugs for Influenza Virus

M2 Protein Blockers – Amantidine and Rimantidine. Inhibit the M2 protein ion channel function (blocks viral uncoating and disassembly during endocytosis). Treat influenza A infections. Therapy initiated in the first 48 hrs can decrease the illness by 1-2 days. Can prevent infection in unvaccinated exposed people.

Neuraminidase Inhibitors – Zanamivir (aerosol) and Oseltamivir (oral). These drugs block the release of virus from infected cells and stop viral spread in the respiratory tract. Effective against influenza A and B. Therapy initiated in the first 48 hrs can decrease the illness by 1-2 days. Also effective in preventing disease.

Ribavirin – a guanosine analog which inhibits Inosine-5-phosphate dehydrogenase and therefore nucleic acid synthesis. Used for RSV in hospitalized children or to treat chronic Hep C along with interferon a .

Drugs for Retroviruses (HIV)

Nucleoside reverse transcriptase inhibitors – nucleoside analogs which competitively inhibit reverse transcriptase at the active site.

DRUG, Generic name brand name – Side Effects:

AZT Zidovudine Retrovir– myelosuppression (anemia, leukopenia), myopathy

DDI Didanosine Videx – peripheral neuropathy (all "D" drugs do this), pancreatitis, and diarrhea

DDC Zalacitabine Hivid - peripheral neuropathy and pancreatitis

D4T Stavudine Zerit – peripheral neuropathy

3TC Lamivudine Epivir – rarely hepatitis, very safe drug but become resistant easily

ABC Abacavir - hypersensitivity syndrome presents in the first few weeks of administration (fever, myalgias, rash) in up to 5% of pts. Once stopped this medication can not be started again (risk of death)

Non-nucleoside reverse transcriptase inhibitors – bind to reverse transcriptase as a non-active site changing the conformation of the enzyme. These drugs are very effective but are only one mutation away from resistance.

Nevirapine and Delaviridine – both cause rash and sometimes Steven’s Johnson syndrome.

Efavirenz – rash, nightmares, and dysphoria (CNS symptoms go away after the initial first few weeks.

Protease inhibitors – block viral polyprotein processing.

Indinavir Crixavan – kidney stone (pts need to drink 8 glasses of H₂O/day)

Ritonavir Norvir – mainly used in combo with other Protease inhibitors because it slows down their metabolism and allows for greater concentrations to be reached and maintained (the difference between TID and BID dosing)

Saquinavir Inverase (hard capsules) Fortavase (newer soft capsules) – poor bioavailability the old formula, diarrhea both formulas, too many pills the new formula.

Nefinavir Viracept – diarrhea, taken with food helps. TID or BID dosing.

Amprenavir – newest, 8 pills BID, but may have less lipid side effects and a slightly different resistance profile.

Principles in anti-Retroviral therapy

Multiple drugs are required, monotherapy in never effective.
The goal of therapy is to drop the viral load to undetectable and keep it there. Monthly checks of viral load and CD4+ counts the first few months to assess
he regimen’s effectiveness. Once stable follow counts and viral loads every 3 months.
When changing therapy, try to use two new drugs to delay the emergence of resistance.
Start therapy when: (1) pts are symptomatic, (2) CD4+ count falls below 500, or (3) the viral load is above 20,000.
Initial regimes – two nucleoside analogs and a protease inhibitor (AZT, 3TC, and Nelfinavir) or two nucleoside analogs and a non-nucleoside reverse transcriptase inhibitor (AZT, 3TC, and Efavirenz).
Pts must be committed to strict adherence to the long term medication regime.

ANTI-RETROVIRAL THERAPY

Decreases mortality and AIDS related complications in pts with AIDS
Decreases the seroconversion rate after HIV-infected needlestick
Decreases the vertical transmission (mom to baby) from HIV infected mothers
Results in clinical improvement in AIDS pts with HIV-Dementia and HIV-Idiopathic thrombocytopenic purpura